Search

Helicobacter pylori (H. pylori) infection is considered as one of the principal risk factors of gastric cancer. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated gastric carcinogenesis. In the canonical STAT3 pathway, phosphorylation of STAT3 on Tyr705 is a major event of STAT3 activation. However, recent studies have demonstrated that STAT3 phosphorylated on Ser727 has an independent function in mitochondria. In the present study, we found that human gastric epithelial AGS cells infected with H. pylori resulted in localization of STAT3 phosphorylated on Ser727 (P-STAT3 Ser727 ), predominantly in the mitochondria. Notably, H. pylori-infected AGS cells exhibited the loss of mitochondrial integrity and increased expression of the microtubule-associated protein light chain 3 (LC3), the autophagosomal membrane-associated protein. Treatment of AGS cells with a mitophagy inducer, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), resulted in accumulation of P-STAT3 Ser727 in mitochondria. In addition, the elevated expression and mitochondrial localization of LC3 induced by H. pylori infection were attenuated in AGS cells harboring STAT3 mutation defective in Ser727 phosphorylation (S727A). We also observed that both P-STAT3 Ser727 expression and LC3 accumulation were increased in the mitochondria of H. pylori-inoculated mouse stomach.

Background: The diagnosis of gastric atrophy is important in the regions where the prevalence of Helicobacter pylori (H. pylori) is high. The assessment of gastric atrophy is impossible in subjects with severe gastric inflammation or inadequate biopsy samples, leading these cases to be categorized as indefinite for atrophy. The aim of this study was to evaluate clinical characteristics of cases reported as indefinite for atrophy., Materials and Methods: We reviewed 3192 gastric biopsies obtained at a single medical center between 2003 and 2017. Cases categorized as indefinite atrophy (n = 1,292) were compared with three groups, the absent atrophy group (n = 755), Operative Link on Gastric Atrophy (OLGA) I-II group (n = 925), and OLGA III-IV group (n = 220), by considering age, sex, smoking, alcohol drinking, salty and spicy food diet, ABO blood type, family history of gastric cancer (GC), and H. pylori infection that are known atrophic gastritis-associated risk factors., Results: Subjects aged ≥65 years (34.9% vs 26.4%, P < 0.001), male (58.9% vs 49.1%, P < 0.001), and H. pylori infected subjects (82.5% vs 63.3%, P < 0.001) were significantly more likely to be categorized into the indefinite atrophy group than absent atrophy group. Subjects with family history of GC (21.9% vs 25.7%, P = 0.031) and positive H. pylori infection (82.5% vs 86.2%, P = 0.019) were significantly less likely to be in the indefinite atrophy group than low-risk OLGA group. Subjects aged ≥65 years (34.9% vs 52.3%, P < 0.001) and current/past smoker (50.9% vs 70.0%, P < 0.001) were significantly more likely to be in the high-risk OLGA group than indefinite atrophy group., Conclusions: The pathological report of indefinite for atrophy suggests a higher plausibility of gastric atrophy than nonassessment due to a simple technical error., (© 2019 John Wiley & Sons Ltd.)

Background/aims: Irsogladine maleate, an enhancer of gastric mucosal protective factors, has demonstrated its efficacy for various gastric mucosal injuries. The aim of this study was to evaluate the efficacy and safety of irsogladine for prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin-induced peptic ulcer and gastritis., Methods: In this multicenter, randomized, double-blind, exploratory clinical trial, 100 patients over 50 years of age who needed continuous NSAIDs or aspirin for more than 8 weeks were randomly assigned to either test group (irsogladine maleate 2 mg, twice daily, 39 patients for full analysis) or placebo group (37 patients for full analysis). Primary outcomes were incidence of peptic ulcer and ratio of modified Lanza score (MLS) 2 to 4. Secondary outcome was the number of acute erosions confirmed by endoscopy at 8 weeks. Adverse effects were also compared., Results: There were no significant differences in gastric protective effects between test and placebo groups. However, two cases of peptic ulcer in the placebo group but none in the test group were observed. These two cases of peptic ulcer were Helicobacter pylori-negative. In addition, H. pylori-negative group showed significant changes in MLS score (p = 0.0247) and edema score (p = 0.0154) after the treatment compared to those before treatment in the test group. There was no significant difference in adverse events between the two groups., Conclusion: The efficacy of irsogladine maleate was found in H. pylori-negative group, suggesting its potential as a protective agent against NSAIDs or aspirin-induced peptic ulcer and gastritis.

Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been well-established methods of treating upper gastrointestinal neoplasia. The aim of this study was to identify the safety and effectiveness of endoscopic treatment for gastric neoplasia within a 2-day hospital stay.Between 2004 and 2015, a total of 914 patients with gastric neoplasia were treated with EMR or ESD within 2 days of hospitalization. The neoplasia sites, en bloc resection rates, pathology, local residual neoplasia rates, and major complications were evaluated retrospectively.The mean age was 63.4 years old, and 636 (69.6%) patients were male. Adenoma was the most common final diagnosis (60.9%), followed by adenocarcinoma (28.9%). The first follow-up endoscopy was performed 4.9 ± 1.1 months after the procedure, and an average of 4.4 endoscopic examinations were performed for 7.16 years (range, 2.1 to 10.2 years). Additional surgery was performed in 11 (1.2%) cases based on post-procedure pathology results. On follow-up endoscopy, a mean of 5.9 months after the procedure, there were 18 residual neoplasia cases (EMR = 13, ESD = 5). Only 4 (0.4%) patients returned to the emergency unit with delayed bleeding, but all 4 cases were successfully controlled with endoscopic treatment. There were no other complications such as delayed perforation or aspiration pneumonia during the 2 days in hospital.EMR and ESD within only 2 days in hospital showed safe and effective outcomes in terms of managing early gastric neoplasia with low complication and local residual rates.

The cascade of gastric cancer, a leading cause of cancer incidence and mortality, is multifactorial. Helicobacter pylori (HP) infection plays a major role in gastric cancer (GC), and there has been an accumulation of data regarding the chemopreventive effect of HP eradication. However, it remains unclear how HP infection causes GC and how HP eradication prevents GC. To clarify this issue, the following approaches were performed in this review article. First, how HP-induced atrophic gastritis (AG) and intestinal metaplasia (IM) provoke the development of GC is shown, followed by how long HP eradication takes to induce a reversible change in AG and IM. Second, epigenetic studies of PTPN6, MOS, DCC, CRK, and VAV1 were performed in noncancerous gastric specimens in terms of HP status. Among these genes, MOS was found to be a possible surrogate marker for GC development. HP eradication decreased aberrant DNA methylation in a gene-specific manner, and MOS played a role in metachronous gastric neoplasms. Third, transforming growth factor-β1 (TGF-β1) and TGF-β1-induced epithelial-mesenchymal transition (EMT) markers were investigated in gastric mucosa. HP infection triggered the TGF-β1-induced EMT pathway and caused the emergence of GC stem cells, such as CD44v8-10. When HP was eradicated, these two pathways were inhibited. Finally, a 2222 cohort study showed that HP eradication significantly decreased the risk of noncardiac GC. Taken together, HP eradication is effective as a primary GC prevention method, and its underlying mechanism includes reversibility of AG and IM, methylation, EMT, and stem cells., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Although there are many guidelines recommending Helicobacter pylori (H. pylori) eradication therapy for atrophic gastritis (AG) and intestinal metaplasia (IM), there have been contradictory reports regarding the reversibility of precancerous lesions such as AG and IM after eradication of H. pylori . There have been many reports that have shown AG seems to improve upon eradication of H. pylori to some extent. In contrast, IM has been regarded as 'the point of no return' according to previous reports. However, as recent studies have suggested the improvement of intestinal metaplasia as well, early eradication therapy for reversible histological status is important and necessary for the prevention of gastric cancer. In this review, we focused on the progress of gastritis resulting in AG and IM mainly by H. pylori , the relationship of AG and IM with gastric cancer, the subtype of IM, and the reversibility of AG and IM by eradication of H. pylori . Finally, we introduced the recent extension of indications for H. pylori eradication with coverage by medical insurance, which was published by the Korean Ministry of Health and Welfare in January 2018.

Background: Little is known about the role of gastric microbiota except for Helicobacter pylori (HP) in human health and disease. We compared the differences of human gastric microbiota according to gastric cancer or control and HP infection status and assessed the role of bacteria other than HP., Methods: Gastric microbiota of 63 antral mucosal and 18 corpus mucosal samples were analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Antral samples were divided into four subgroups based on HP positivity in pyrosequencing and the presence of cancer. The analysis was focused on bacteria other than HP, especially nitrosating or nitrate-reducing bacteria (NB). The changes of NB in antral mucosa of 16 subjects were followed up., Results: The number of NB other than HP (non-HP-NB) was two times higher in the cancer groups than in the control groups, but it did not reach statistical significance. The number of non-HP-NB tends to increase over time, but this phenomenon was prevented by HP eradication in the HP-positive control group, but not in the HP-positive cancer group., Conclusion: We could not find the significant role of bacteria other than HP in the gastric carcinogenesis., (© 2016 John Wiley & Sons Ltd.)

Background: The aim of this study was to identify the risk factors for residual/recurrent tumors in patients with a tumor-positive lateral resection margin (LRM+) after endoscopic resection of early gastric cancer (EGC) and to establish the criteria for performing additional treatment., Methods: A retrospective analysis was performed on consecutive patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of EGC. Clinicopathological characteristics and risk factors for residual/recurrent tumor in LRM+ patients were analyzed., Results: Eighty-two patients (84 lesions) with LRM+ after EMR (n = 45) or ESD (n = 39) were enrolled. Forty patients underwent additional gastrectomy or ESD, and 44 were closely observed. The residual/recurrent tumor rate was 34.5 % (29 of 84 lesions). Univariate analysis found that the residual/recurrent tumor was associated with the endoscopic resection type (EMR), undifferentiated histology, number of involved directions, rate of lateral resection margin involvement and the total length (mm) of the lateral resection margin involved by the tumor. In multivariate logistic regression analysis, undifferentiated histology and rate (%) were independent risk factors (odds ratio [OR] 5.28, 95 % confidence interval [CI] 1.13-24.72, p = 0.035 and OR 1.08, 95 % CI 1.03-1.14, p = 0.004, respectively). Clinicopathological factors that were identified from the univariate and multivariate analyses were scored in order to predict residual/recurrent tumors., Conclusion: We suggest a scoring system for additional treatment in patients with LRM+ after endoscopic resection of EGC based on the development of residual/recurrent tumors. This scoring system enables a more detailed selection of cases and may be useful in determining further treatment.

Background: Changes in CDX1/CDX2 in gastric mucosae following Helicobacter pylori eradication have not been clarified yet., Aims: To evaluate the changes in CDX1/CDX2 expression after H. pylori eradication, in relation to the reversibility of intestinal metaplasia (IM)., Methods: Time course of CDX1/CDX2 expressions was investigated in 176 subjects with various gastroduodenal disorders. Among them, 132 patients were H. pylori positives; H. pylori were eradicated in 107 of them; 13 failed to eradicate; and 12 did not receive H. pylori eradication therapy. Forty-four subjects were H. pylori negatives. Expression levels in CDX1 and CDX2 from noncancerous gastric mucosae of the corpus, as well as the histologic findings of gastric mucosae, were evaluated during the follow-up., Results: Average follow-up duration was 33.7 months (range 2-97 months). Expression levels in both CDX1 and CDX2 mRNAs were correlated with IM grade in the corpus (ρ = 0.633 and 0.554, respectively, all P < 0.001). Changes in CDX1/CDX2 mRNA expressions following H. pylori eradication showed only insignificant results; IM grade at the antrum and corpus showed a tendency to decrease after H. pylori eradication without statistical significance (P > 0.05). However, histologic improvement of IM at the corpus was associated with a decrease in CDX2 mRNA expression during the follow-up (linear mixed model, P for slope = 0.015)., Conclusions: In this study, eradication of H. pylori did not show any beneficial effects on aberrant CDX1/CDX2 expressions or IM. Reversibility of IM may be associated with a decrease in CDX2 mRNA expression.

Background: Sequencing of 16S ribosomal RNA (rRNA) gene has improved the characterization of microbial communities. It enabled the detection of low abundance gastric Helicobacter pylori sequences even in subjects that were found to be H. pylori negative with conventional methods. The objective of this study was to obtain a cutoff value for H. pylori colonization in gastric mucosa samples by pyrosequencing method., Materials and Methods: Gastric mucosal biopsies were taken from 63 subjects whose H. pylori status was determined by a combination of serology, rapid urease test, culture, and histology. Microbial DNA from mucosal samples was amplified by PCR using universal bacterial primers. 16S rDNA amplicons were pyrosequenced. ROC curve analysis was performed to determine the cutoff value for H. pylori colonization by pyrosequencing. In addition, temporal changes in the stomach microbiota were observed in eight initially H. pylori-positive and eight H. pylori-negative subjects at a single time point 1-8 years later., Results: Of the 63 subjects, the presence of H. pylori sequences was detected in all (28/28) conventionally H. pylori-positive samples and in 60% (21/35) of H. pylori-negative samples. The average percent of H. pylori reads in each sample was 0.67 ± 1.09% in the H. pylori-negative group. Cutoff value for clinically positive H. pylori status was approximately 1.22% based on ROC curve analysis (AUC = 0.957; p < .001). Helicobacter pylori was successfully eradicated in five of seven treated H. pylori-positive subjects (71.4%), and the percentage of H. pylori reads in these five subjects dropped from 1.3-95.18% to 0-0.16% after eradication., Conclusion: These results suggest that the cutoff value of H. pylori sequence percentage for H. pylori colonization by pyrosequencing could be set at approximately 1%. It might be helpful to analyze gastric microbiota related to H. pylori sequence status., (© 2015 John Wiley & Sons Ltd.)

Background: Transforming growth factor-β1 (TGF-β1) has dual roles inhibiting and promoting carcinogenesis. Although many researchers have conducted association studies between TGFB1 C-509T polymorphism and the risk of developing gastric cancer, the results are not uniform., Methods: We genotyped 1028 gastric cancer patients and 958 controls by the polymerase chain reaction-restriction fragment length polymorphism method. Immunohistochemistry was performed to assess the expression of TGF-β1 in the cancer and noncancerous tissues of 120 gastric cancer patients. mRNA expression was also measured in noncancerous gastric mucosa by qRT-PCR in the 282 subjects., Results: The CT genotype in the TGFB1 C-509T polymorphism was associated with an increased risk of gastric cancer development (adjusted OR 1.35, 95 % CI 1.07-1.71, P = 0.013), especially for intestinal-type cancer (adjusted OR 1.43, 95 % CI 1.08-1.90, P = 0.014). More frequent TGF-β1 expression was found in the center of cancer tissue in the TGFB1-509T carrier group than in the others (90.5 % vs. 72.2 %, P = 0.010). T-carriers also presented higher expression level of gastric TGF-β1 mRNA than non T-carriers (median 1.29 vs. 0.80, P = 0.004) when they were infected by H. pylori. Cancer patients showed elevated gastric TGFB1gene expression compared to the control group (median 1.22 vs. 0.89, P = 0.009)., Conclusions: The carcinogenic effect of TGF-β1 might be associated with increased gastric TGF-β1 expression in subjects with the T allele of TGFB1-509.

We know little concerning the expression of transforming growth factor-β1 (TGF-β1) and TGF-β1-induced epithelial-mesenchymal transition (EMT) markers in gastric mucosa and their changes after eradication of Helicobacter pylori infection have not yet been clarified. In the present study, we compared the time course of messenger RNA (mRNA) expression of TGF-β1 and five EMT markers (Twist, Snail, Slug, vimentin and E-cadherin) in 111 controls, 55 patients with gastric dysplasia and 71 patients with early gastric cancer, following eradication of H.pylori. mRNA levels in non-cancerous gastric mucosa were measured using quantitative real time-polymerase chain reaction and the histologic findings of gastric mucosa were compared before and after eradication. The average duration of follow-up was 46.7 months (6.0-112.4). The levels of TGF-β1, Twist, Snail, Slug and vimentin mRNA, in addition to levels of CD44 detected by immunohistochemistry, showed all up-regulation in patients with dysplasia or early gastric cancer compared with controls (P < 0.05); moreover, the mRNA levels of E-cadherin, an epithelial marker, were decreased in these patients compared with the control group (P < 0.001). Eradication of H.pylori reduced the expression of TGF-β1, Twist, Snail, Slug and vimentin mRNA (P-value for slope <0.001), as well as the immunohistochemical expression of CD44 (P = 0.014), whereas it enhanced the expression of E-cadherin (P-value for slope < 0.05). Thus, H.pylori infection may trigger the TGF-β1-induced EMT pathway and the emergence of gastric cancer stem cells (CSCs). Its eradication may prevent the carcinogenesis of gastric cancer by inhibiting these two pathways., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/aims: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID., Methods: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated., Results: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively., Conclusions: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

Gastric mucosal inflammation can develop after challenge with noxious stimuli such as alcohol. Specially, alcohol stimulates the release of inflammatory cytokines but does not increase gastric acid secretion, leading to gastric mucosal damage. The plant sterol guggulsterone and its novel derivative GG-52 have been reported to inhibit nuclear factor-κB (NF-κB) signaling in intestinal epithelial cells and experimental colitis. In the present study, we investigated the anti-inflammatory effects of GG-52 on gastric epithelial cells and on ethanol-induced gastric mucosal inflammation in mice. GG-52 inhibited the expression of interleukin-8 (IL-8) in gastric epithelial AGS and MKN-45 cell lines stimulated with tumor necrosis factor (TNF)-α in a dose-dependent manner. Pretreatment with GG-52 suppressed TNF-α-induced activation of IκB kinase (IKK) and NF-κB signaling in MKN-45 cells. In contrast, the inactive analog GG-46 did not produce significant changes in IL-8 expression or NF-κB activation. In a model of ethanol-induced murine gastritis, administration of GG-52 significantly reduced the severity of gastritis, as assessed by macroscopic and histological evaluation of gastric mucosal damage. In addition, the ethanol-induced upregulation of chemokine KC, a mouse homolog of IL-8, and phosphorylated p65 NF-κB signals were significantly inhibited in murine gastric mucosa pretreated with GG-52. These results indicate that GG-52 suppresses NF-κB activation in gastric epithelial cells and ameliorates ethanol-induced gastric mucosal lesions in mice, suggesting that GG-52 may be a potential gastroprotective agent.

Background and Aim: Gastric mucosal expression of interleukin (IL)-1β may alter acid secretion and influence the development of gastroesophageal reflux disease (GERD). The relationship of gastric mucosal IL-1β level and GERD was evaluated in the Korean population., Methods: Genotypes of IL-1B-511 and IL-1RN VNTR polymorphism and clinical characteristics were analyzed in 44 patients with erosive esophagitis (EE), 32 patients with minimal change lesions (MCL), 54 patients with non-erosive reflux disease (NERD) and 113 controls. Gastric mucosal IL-1β levels were measured by enzyme linked immunosorbent assay., Results: Significant differences were found between the EE and the control group with respect to sex, body mass index, and Helicobacter pylori infection. On the other hand, the MCL and the NERD group showed similar characteristics to that of the control group. IL-1B-511 genetic polymorphism showed relationship with gastric mucosal IL-1β levels. That is, T/T group (112.4 ± 14.3 pg/mg) had higher IL-1β level than C/C group (59.5 ± 11.6, P = 0.011). T carriers (92.8 ± 7.6 pg/mg) showed higher level than T non-carrier group (P = 0.050). In addition, mucosal IL-1β level of the EE group (52.3 ± 9.9 pg/mg) was lower than that of the control (107.8 ± 12.6 pg/mg, P = 0.001), the MCL (103.1 ± 13.5 pg/mg, P = 0.004), and the NERD group (83.8 ± 14.5 pg/mg, P = 0.079). However, genetic polymorphisms of IL-1B-511 and IL-1RN VNTR did not reach statistical significance among four groups., Conclusion: Gastric mucosal IL-1β level might be one factor in the development of GERD., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Conjugated linoleic acids (CLA) produced by Lactobacillus acidophilus was reported to decrease the activation of nuclear factor-kappa B. CLA was suggested as one of the anti-inflammatory molecular mechanisms of probiotics. In the present study, the effects of CLA on H. pylori-induced multiple responses were evaluated. IL-8, TNF-α and iNOS were measured in mRNA and/or protein levels in AGS cells after pretreatment with CLA or CLA-containing conditioned medium (CM) produced by Lactobacillus acidophilus or Lactobacillus plantarum. The increased expressions of IL-8 mRNA/protein and TNF-α mRNA were significantly suppressed by pretreatment with CM or CLA. The levels of IL-8 protein and TNF-α mRNA were suppressed by CM pretreatment better than CLA. The expression of iNOS mRNA was also significantly inhibited by CM pretreatment. These results suggest that the suppression of multiple mediators by CLA-containing CM plays a key role in the anti-inflammatory and anti-carcinogenic effects of probiotics on H. pylori infection., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/aims: There have been few reports comparing pre and postoperative prevalence of Helicobacter pylori infection and gastritis in patients with gastric cancer surgery., Methodology: Seventy patients with primary gastric cancer were identified to be infected with Helicobacter pylori preoperatively and tested for Helicobacter pylori infection after subtotal gastrectomy. We analyzed changes in Helicobacter pylori infectivity and histological features of gastric mucosa., Results: The overall spontaneous regression rate of Helicobacter pylori infection was 38.6% (27/70). The mean time between surgery and follow-up tests was 1.02±0.5 years. The activity and chronic inflammation scores were significantly decreased in regression group. In non-regression group, there was no significant difference in activity scores, but the chronic inflammation score was significantly increased. There were no significant changes in atrophic gastritis and intestinal metaplasia scores in either group. The grade of Helicobacter pylori infection was significantly decreased in non-regression group., Conclusions: The spontaneous regression rate of Helicobacter pylori infection after subtotal gastrectomy was 38.6% (27/70), it occurred in larger scale of patients and it occurred earlier (1.02±0.5 years) than in previous studies. We suggest that further prospective study on spontaneous regression rate of Helicobacter pylori infection after subtotal gastrectomy and its mechanism is needed in the future.

Aberrant DNA methylation is frequently found during gastric carcinogenesis. Recently, we identified potential methylation markers important for Helicobacter pylori-induced gastric carcinogenesis using an Illumina methylation chip assay. In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non-neoplastic gastric specimens using quantitative methylation-specific PCR in patients with GC (n = 207) and their age- and gender-matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy-based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation levels in MOS remained increased in patients with past H. pylori infection compared to H. pylori-negative subjects (p < 0.001). Methylation levels in MOS in non-neoplastic gastric mucosae increased in the presence of GC, regardless of H. pylori infection status (p < 0.01). Methylation levels in all genes but DCC decreased significantly in GC specimens compared to neoplastic gastric mucosae (p < 0.01); however, methylation levels in GC tissues were not correlated with those in their background gastric mucosae. Hypomethylation of MOS in GC tissues was associated with tumour invasion, nodal metastasis, and undifferentiated histology (p < 0.05). To summarize, among the candidate genes, DNA methylation of MOS may reflect the duration of H. pylori exposure and may be a marker for the development of GC., (Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Context: Helicobacter pylori infection is primarily acquired during childhood and persists throughout life in the absence of eradication with antibiotics. Helicobacter pylori infection induces methylation in the promoter CpG island loci in gastric epithelial cells. Thus, aberrant CpG island hypermethylation in gastric epithelial cells likely occurs early in life, although there are no existing data supporting this notion., Objectives: To identify whether aberrant CpG island hypermethylation occurs in pediatric stomach mucosa in association with H pylori infection and to compare methylation profiles of samples from pediatric and adult stomach tissues., Design: We analyzed pediatric (n = 47) and adult (n = 38) gastric mucosa samples for their methylation status in 12 promoter CpG island loci using the MethyLight assay and compared the number of methylated genes and the methylation levels in individual genes between H pylori -positive and H pylori -negative sample results and between pediatric and adult samples., Results: The average number of methylated genes was significantly higher in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (3.4 versus 0.3, P < .001) and in H pylori -infected adult samples than in H pylori -negative adult samples (7.6 versus 0.9, P < .001). Seven genes showed significantly higher methylation levels in H pylori -infected pediatric samples than in H pylori -negative pediatric samples (all values were P < .05)., Conclusions: These results indicate that CpG island hypermethylation occurs in pediatric gastric mucosa in association with H pylori infection and that the genes affected by H pylori -associated hypermethylation were similar in pediatric and adult samples.

Background and Aims: To determine genome-wide DNA methylation profiles induced by Helicobacter pylori (H. pylori) infection and to identify methylation markers in H. pylori-induced gastric carcinogenesis., Methods: Gastric mucosae obtained from controls (n = 20) and patients with gastric cancer (n = 28) were included. A wide panel of CpG sites in cancer-related genes (1505 CpG sites in 807 genes) was analyzed using Illumina bead array technology. Validation of the results of Illumina bead array technique was performed using methylation-specific PCR method for four genes (MOS, DCC, CRK, and PTPN6)., Results:  The Illumina bead array showed that a total of 359 CpG sites (269 genes) were identified as differentially methylated by H. pylori infection (p < .0001). The correlation between methylation-specific PCR and bead array analysis was significant (p < .0001, Spearman coefficient = 0.5054). Methylation profiles in noncancerous gastric mucosae of the patients with gastric cancer showed quite distinct patterns according to the presence or absence of the current H. pylori infection; however, 10 CpG sites were identified to be hypermethylated and three hypomethylated in association with the presence of gastric cancer regardless of H. pylori infection (p < .01)., Conclusions:  Genome-wide methylation profiles showed a number of genes differentially methylated by H. pylori infection. Methylation profiles in noncancerous gastric mucosae from the patients with gastric cancer can be affected by H. pylori-induced gastritis. Differentially methylated CpG sites in this study needs to be validated in a larger population using quantitative methylation-specific PCR method., (© 2011 Blackwell Publishing Ltd.)

Aging changes in the stomach lead to a decreased capacity for tissue repair in response to gastric acid. The aim of this study was to determine the mechanism associated with the increased susceptibility to injury of aging mucosa including reactive oxygen species (5), apoptosis, angiogenesis, and sensory neuron activity. Fischer 344 rats at four different ages (6, 31, 74 wk, and 2 yr of age) were studied. The connective tissue indicators [salt-soluble collagen and sulfated glycosaminoglycan (sGAG)], lipid hydroperoxide (LPO), myeloperoxidase (MPO), and hexosamine were assessed. We also evaluated the expression of early growth response-1 (Egr-1), phosphatase and tension homologue deleted on chromosome 10 (PTEN), caspase-9 (index of apoptosis), VEGF (index of angiogenesis), calcitonin gene-related peptide (CGRP, index of sensory neurons), and neuronal nitric oxide synthase (nNOS). The histological connective tissue area in the lower part of rat gastric mucosa increased with aging, with increase of salt-soluble collagen and sGAG. LPO and MPO in old rats were significantly greater than in the young rats, whereas hexosamine was significantly reduced. The old gastric mucosa had increased expression of Egr-1, PTEN, and caspase-9, whereas the VEGF, CGRP, and nNOS expression were significantly reduced. These results indicate that the lower part of rat gastric mucosa was found to be replaced by connective tissue with accumulation of oxidative products with aging. In addition, impairment of apoptosis, angiogenesis, and sensory neuron activity via the activation of Egr-1 and PTEN might increase the susceptibility of gastric mucosa to injury during aging.

Cochinchina momordica seed extract (SKMS10), which is composed of the major compounds momordica saponins, has been evaluated for its gastroprotective effects in rat models of acute gastric mucosal damage. Ethanol and water immersion restraint stress (WRS) induced gastric damage, including hemorrhages and edema, was significantly attenuated by pretreatment with SK-MS10. In addition, SK-MS10 reduced increases of mucosal myeloperoxidase (MPO), IL-1β, and TNFα levels and the expression of cPLA(2), and 5-LOX induced by ethanol or WRS. SK-MS10 also increased hexosamine, adherent mucus, and the expression of MUC5AC. Furthermore, SK-MS10 enhanced the mucosal expression of the CGRP gene and its serum levels.N(G)-methyl L-arginine (L-NMMA) or capsaicin desensitization reversed the SK-MS10-induced gastroprotection effect. These results suggest that SK-MS10 is a gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, downregulating cPLA(2), 5-LOX, and increasing the synthesis of mucus. Furthermore, CGRP-NO pathway was found to play an important role in these gastroprotective effects of SK-MS10., (© Springer Science+Business Media, LLC 2009)

Background and Aim: Infection of Helicobacter pylori is viewed as a major driver of progression to the precancerous state or to gastric cancer. This study was performed to investigate the effect of H. pylori infection on gastric cancer development and to determine to what extent H. pylori eradication is likely to reduce the prevalence of gastric cancer., Methods: Gastric cancer development was investigated in 1790 Korean subjects who underwent gastroscopy and H. pylori testing between 1992 and 1998. The effects of H. pylori-positive and eradicated states on gastric cancer development were analyzed., Results: Gastric cancer developed in 5 of the study cohort during a mean follow-up period of 9.4 years. All of these patients were positive for H. pylori infection, and 4 of the 5 had antral intestinal metaplasia (IM) at the time of study enrollment. One of these 5 patients was in an eradicated state when the gastric cancer was diagnosed, and had histologic IM before eradication therapy was performed. Gastric cancer was found to develop 10.9 times more frequently in the presence of IM than in its absence., Conclusions: The present study shows a close relationship between H. pylori infection and IM, and between IM and the development of gastric cancer. In addition, our finding suggests that chronic H. pylori infection looks like an important risk factor for the development of gastric cancer in Korea, where the prevalence of H. pylori remains high. This study indicates that to prevent gastric cancer H. pylori eradication is best performed before the development of IM.

Aims: This study was performed to determine the gastric distributions of MUC5AC and MUC6 depending on Helicobacter pylori (H. pylori) infection, and to evaluate whether the expressions of MUC5 and MUC6 change in H. pylori-associated gastroduodenal diseases. In addition, MUC5AC and MUC6 expressional changes were investigated before and after H. pylori eradication., Methods: In the 224 individuals (136 H. pylori-positive and 88 H. pylori-negative) who came from control (N=48), duodenal ulcer (N=35), benign gastric ulcer (N=61), dysplasia plus stomach cancer (N=80) groups, MUC5AC and MUC6 expressions were determined by immunohistochemical staining in the antrum and body, respectively. This staining for MUC5AC and MUC6 were reperformed in 113 of the 136 H. pylori-positive patients after successful H. pylori eradication by proton pump inhibitor-based triple therapy., Results: (1) No difference was found between the H. pylori-positive and negative groups in terms of MUC5AC expression. In contrast, MUC6 expression was significantly lower in the H. pylori-positive group than in the H. pylori-negative group in the gastric body. Moreover, reduced MUC6 expression increased to the H. pylori-negative level after eradication. (2) Expressions of MUC5AC and MUC6 were significantly lower in the dysplasia plus cancer group than those of control in case of H. pylori positive. Similarly, MUC5AC and MUC6 expressions were significantly lower in the presence of atrophic gastritis with intestinal metaplasia in case of H. pylori positive. (3) Aberrant expressions of MUC6 in foveolar cells were observed in both antrum (11.3%) and body (5.3%) only in the H. pylori-positive group, but this reverted to normal after H. pylori eradication., Conclusion: These results suggest that H. pylori infection causes alterations of mucin expression, closely related with the development of gastric atrophy with intestinal metaplasia, probably contributing to carcinogenesis.

This study was performed to evaluate the implication of anti-H. pylori IgG positivity when CLOtest, histological test, and culture in the antrum and body are all negative, and to find out the specific disease category that is more affected by the hostile relationship of atrophic gastritis and intestinal metaplasia (IM) with H. pylori. Four hundred thirty-six patients (84 controls, 69 with duodenal ulcer, 96 with benign gastric ulcer, 43 with dysplasia, 144 with gastric cancer), who had not received any eradication therapy, were divided into three groups according to H. pylori test: CLOtest or histological H. pylori-positive group (group A; 294 cases), only anti-H. pylori IgG-positive group (group B; 62 cases), and anti-H. pylori IgG-negative group (group C; 80 cases). The grade of neutrophil and monocyte infiltration, atrophic gastritis, and IM was compared according to the updated Sydney system classification. Neutrophil and monocyte infiltrations were significantly severe in the group A. In contrast, the grade of atrophic gastritis and IM in the antrum was significantly higher in group B than the other two groups, A or C. When patients were divided according to the disease outcome in each group, the grade of IM in the body was statistically higher only in the patients with cancer or dysplasia in group B. These results suggest that anti-H. pylori IgG positivity with all negative invasive H. pylori tests represents past infection with H. pylori rather than a false negative, especially in the case of dysplasia and gastric cancer.

The mucus layer that covers gastric mucosa is a powerful barrier that protects tissues from the hazardous gastric environment; however, the role of each gastric MUC type, such as MUC1, MUC5AC, and MUC6, has not been evaluated. The purpose of this study is to identify the MUC type, which plays a predominant role in this protective process by use of geranylgeranylacetone (GGA), a promising cytoprotective agent. In addition, the mechanism of mucus secretion promoted by GGA was investigated. Rat gastric mucosal damage was provoked using ethanol, and GGA was pretreated 1 hour before ethanol. GGA was found to significantly protect rats from ethanol-induced gastric damage by increasing mucus levels, MUC5AC and MUC6, especially at ethanol-induced ulcer margins, but not by MUC1. When expression of heat shock protein 70 (HSP70) and neuronal nitric oxide synthase (nNOS) was evaluated by Western blotting, both were found to be increased in GGA-treated ethanol rats. In addition, the cytoprotective effect of GGA was blocked by L-NMMA, a nonspecific NOS inhibitor, but not blocked by aminoguanidine, a specific inducible nitric oxide synthase inhibitor, thus indicating the participation of nNOS. In conclusion, GGA protected ethanol-induced gastric damage by upregulating MUC5AC and MUC6 rather than MUC1. In addition, HSP70 and nNOS were found to be involved in GGA cytoprotection, probably by increasing mucus production or secretion.

Background: Helicobacter pylori stimulates nuclear factor-kappa B (NF-kappa B) activation and chemokine interleukin-8 (IL-8) expression in gastric epithelial cells. Ecabet sodium (ecabet), a locally acting antiulcer drug, is known to have anti-H. pylori activity. However, there is little understanding of how ecabet induces anti-inflammatory activity in gastric epithelial cells infected with H. pylori. The aim of this study was to investigate the effects of ecabet on IL-8 gene expression and NF-kappa B activation in human gastric epithelial cells infected with H. pylori., Materials and Methods: After Hs746T, MKN-45, or SNU-5 gastric epithelial cell lines had been infected with cagA+cytotoxin+H. pylori in the presence of ecabet, IL-8 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction, and IL-8 secretion was measured by enzyme-linked immunosorbent assay. NF-kappa B and inhibitory kappa B-alpha (I kappa B alpha) signals were assayed by electrophoretic mobility shift assay and Western blot, respectively. The activation of NF-kappa B and IL-8 reporter genes was determined by luciferase assay., Results: Ecabet showed no antimicrobial activiy against Gram-positive or -negative bacteria. However, ecabet inhibited transcription of the IL-8 gene and secretion of IL-8 by gastric epithelial cells infected with H. pylori at a concentration of 5 micro g/ml. Moreover, ecabet inhibited the activation of NF- kappa B and the degradation of I kappa B alpha in gastric epithelial cells in response to H. pylori infection. In addition, the NF-kappa B signal inhibited by ecabet was comprised predominantly of heterodimers of p65/p50., Conclusions: Ecabet inhibited H. pylori-induced IL-8 gene transcription and secretion by suppressing the NF-kappa B signal. This inhibition might be one pathway by which ecabet exerts its anti-inflammatory effect on H. pylori-induced gastric inflammation.

Helicobacter pylori infection changes gastric microbiota profiles. However, it is not clear whether H. pylori eradication can restore the healthy gastric microbiota. Moreover, there has been no study regarding the changes in gastric microbiota with aging. The objective of this study was to investigate the changes in gastric corpus microbiota with age and following H. pylori eradication. Changes in corpus mucosa-associated microbiota were evaluated in 43 individuals with endoscopic follow-up > 1 year, including 8 H. pylori -uninfected and 15 H. pylori -infected subjects with no atrophy/metaplasia by histology and pepsinogen I/II ratio > 4.0; 17 H. pylori -infected subjects with atrophy/metaplasia and pepsinogen I/II ratio < 2.5; and 3 subjects with atrophy/metaplasia, no evidence of active H. pylori infection, negative for anti- H. pylori immunoglobulin G (IgG) antibody testing, and no previous history of H. pylori eradication. Successful H. pylori eradication was achieved in 21 patients. The gastric microbiota was characterized using an Illumina MiSeq platform targeting 16S ribosomal DNA (rDNA). The mean follow-up duration was 57.4 months (range, 12–145 months), and median follow-up visit was 1 (range, 1–3). Relative abundance of Lactobacillales and Streptococcus was increased with atrophy/metaplasia. In H. pylori -uninfected subjects (n = 8), an increase in Proteobacteria (Enhydrobacter , Comamonadaceae, Sphingobium); a decrease in Firmicutes (Streptococcus , Veillonella), Fusobacteria (Fusobacterium), Nocardioidaceae, Rothia , and Prevotella; and a decrease in microbial diversity were observed during the follow-up (p trend < 0.05). In 10 of 21 subjects (47.6%), H. pylori eradication induced restoration of microbial diversity; however, a predominance of Acinetobacter with a decrease in microbial diversity occurred in 11 subjects (52.3%). The presence of atrophy/metaplasia at baseline and higher neutrophil infiltration in the corpus were associated with the restoration of gastric microbiota after successful eradication, whereas a higher relative abundance of Acinetobacter at baseline was associated with the predominance of Acinetobacter after H. pylori eradication (p < 0.05). To conclude, in H. pylori- uninfected stomach, relative abundance of Proteobacteria increases, relative abundance of Firmicutes and Fusobacteria decreases, and microbial diversity decreases with aging. H. pylori eradication does not always restore gastric microbiota; in some individuals, gastric colonization by Acinetobacter species occurs after anti- Helicobacter treatment. [ABSTRACT FROM AUTHOR]

Genome-wide association studies of gastric cancer (GC) cases have revealed common gastric cancer susceptibility loci with low effect size. We investigated rare variants with high effect size via whole-exome sequencing (WES) of subjects with familial clustering of gastric cancer. WES of DNAs from the blood of 19 gastric cancer patients and 36 unaffected family members from 14 families with two or more gastric cancer patients were tested. Linkage analysis combined with association tests were performed using Pedigree Variant Annotation, Analysis, and Search Tool (pVAAST) software. Based on the logarithm of odds (LOD) and permutation-based composite likelihood ratio test (CLRT) from pVAAST, MUC4 was identified as a predisposing gene (LOD P-value = 1.9×10−5; permutation-based P-value of CLRT ≤ 9.9×10−9). In a larger cohort consisting of 597 GC patients and 9,759 healthy controls genotyped with SNP array, we discovered common variants in MUC4 regions (rs148735556, rs11717039, and rs547775645) significantly associated with GC supporting the association of MUC4 with gastric cancer. And the MUC4 variants were found in higher frequency in The Cancer Genome Atlas Study (TCGA) germline samples of patients with multiple cancer types. Immunohistochemistry indicated that MUC4 was downregulated in the noncancerous gastric mucosa of subjects with MUC4 germline missense variants, suggesting that loss of the protective function of MUC4 predisposes an individual to gastric cancer. Rare variants in MUC4 can be novel gastric cancer susceptibility loci in Koreans possessing the familial clustering of gastric cancer. [ABSTRACT FROM AUTHOR]

Background To compare clinicopathologic and molecular characteristics of low-grade gastric mucosa-associated lymphoid tissue lymphoma depending on Helicobacter pylori positivity and to find out a predictive factor for unresponsiveness to Helicobacter pylori eradication therapy in Korea. Methods A total of 53 Helicobacter pylori-positive and 13 negative mucosa-associated lymphoid tissue lymphoma patients were enrolled, and tissues from 21 patients were investigated to examine the presence of t(11;18)(q21;q21) with fluorescence in situ hybridization. Clinicopathologic features such as the endoscopic appearance, dominant site of lesion, depth of invasion, clinical stage, and the existence of MALT1 gene rearrangement were compared between these two groups. Fifty-six patients who underwent H. pylori eradication therapy were divided into responder and nonresponder groups. The two groups were analyzed to calculate odds ratios for resistance to the eradication. Results Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma patients averaged a more advanced clinical stage than H. pylori-positive ( p = .023) patients. The frequency of t(11;18)/ API2- MALT1 did not differ between H. pylori-positive (45.5%) and H. pylori-negative cases (55.6%). Thirty-eight of 51 (74.5%) H. pylori-positive patients achieved complete regression after the eradication, while 2 of 5 (40%) H. pylori-negative patients obtained regression. Presence of lesions in both distal and proximal parts of stomach ( p = .041) and bearing of t(11;18)(q21;q21) ( p = .007) were predictors for nonresponsiveness for H. pylori eradication. Conclusions Helicobacter pylori eradication could be performed as a primary therapy regardless of H. pylori status, and assessing t(11;18)/ API2- MALT1 would be considered after failure to remission by H. pylori eradication. [ABSTRACT FROM AUTHOR]

The p53 gene has been referred to as 'the guardian of the genome' because it controls apoptosis and cell cycle arrest. The purpose of this study was to evaluate the association of p53 codon 72 genetic polymorphism and the p53 immunohistochemistry with Helicobacter pylori-associated gastroduodenal diseases, including gastric cancer. This study included 1,852 subjects: controls and patients with gastric cancer, dysplasia, benign gastric ulcers, and duodenal ulcers (DU). Biallelic polymorphism was genotyped by restriction fragment length polymorphism. Immunohistochemical analysis for the detection of mutant type p53 expression was performed. The frequency of the Pro/Pro allele of the p53 codon 72 was higher in the patients with H. pylori-positive dysplasia than in controls (OR: 2.3, 95% CI: 1.3-4.3), but it was less frequent among patients with a H. pylori-positive DU (OR: 0.5, 95% CI: 0.3-0.8). However, there was no significant association with gastric cancer, including the location, stage, or histological type of gastric cancer. Expression of a mutant type of p53 protein was detected in 6.3% of dysplastic tissues and 26.5% of cancerous tissues compared 0% in the controls. Positive expression was higher in the intestinal type of cancer (34.9%) than in the diffuse type (15.0%; P = 0.001). These results suggest that genetic polymorphism of p53 codon 72 played a role in the determination of H. pylori-associated gastroduodenal diseases, but p53 immunostaining did not correlate with those of the p53 genetic polymorphism analysis. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate whether or not the eradication of H. pylori could lead to the regression of intestinal metaplasia (IM) in patients with either duodenal ulcer (DU) or benign gastric ulcer (BGU). The initial antral IM grade was 0.21 in the 72 patients of the H. pylori-eradicated DU group, this decreased to 0.17, 0.14, 0.13, and 0.09 after periods of four weeks, one year, two years, and four years, respectively, but without statistical significance. In the corpus of the DU group, where IM grade was low (0.02), there was no detectable change in IM. The initial antral IM grade of 0.69 in the 41 patients of the H. pylori-eradicated BGU group decreased substantially to 0.61, 0.44, and 0.39 after periods of four weeks and one and two years, respectively, but again without statistical significance. The initial corporal IM grade of the BGU group of 0.27 decreased to 0.20, 0.15, and 0.06 after periods of four weeks and one and two years, again without statistical significance. In contrast, the IM grades of the noneradicated DU group (N = 20) and the BGU group (N = 16) showed nearly no change in the antrum and corpus. Gastritis grades of antrum and corpus in the H. pylori-eradicated DU or BGU group significantly decreased with respect to time (P = 0.0001), but there were no significant changes in the corresponding noneradicated groups. Although there was no statistical significance, IM decreased in the antrum and corpus of the stomach with BGU and in antrum of those with DU over a two to four-year period after H. pylori eradication, suggesting the possible reversibility of IM. [ABSTRACT FROM AUTHOR]